Method and device for enhanced delivery of a biologically active agent through the spinal spaces into the central nervous system of a mammal

ABSTRACT

A delivery method and implantable apparatus that allows for controlled, enhanced and (pre)-programmable administration of a biologically active agent into the spinal structures and/or the brain via the epidural space of a mammal, particularly of a human being and including a feedback regulated delivery method and apparatus specifically in the treatment of neurological diseases and chronic pain.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 09/197,133filed Nov, 20, 1998, now U.S. Pat. No. 6,410,046: a continuation-in-partof U.S. Ser. No. 09/077,123 filed May 20, 1998, now U.S. Pat. No.6,678,553 and continuation-in-part of PCT/EP96/05086 of Nov, 19, 1996.

FIELD OF THE INVENTION

The present invention relates to a delivery method and implantableapparatus that allows for controlled, enhanced and (pre)-programmableadministration of a biologically active agent into the spinal structuresand/or the brain via the epidural space of a mammal, particularly of ahuman being.

BACKGROUND OF THE INVENTION

Currently, there are a large number of methods and devices available todeliver intraspinal medications and the majority of them are based oncontinuous infusion by means of spinal catheters. Mostly the drugs forspinal delivery are anaesthetics. Presently two types of spinalanaesthesia techniques are routinely employed in surgical procedures.The two techniques are epidural and subarachnoid or intrathecalanaesthesia. With epidural anaesthesia, a catheter is usually placed inthe spinal epidural space and the anaesthetics are administered throughthe catheter. U.S. Pat. No. 4,349,023 to Gross describes an example ofsuch an epidural procedure. The advantage of this technique is that itallows for continuous administration over an extended period of time.There are however also disadvantages associated to this technique suchas for instance, the non-uniform and often unpredictable distribution ofthe anaesthetics in the epidural space, which can be attributed to thecharacteristics of the epidural tissue, which is composed of fatty andfibrous material.

In contrast to the epidural space, the subarachnoid or intrathecal spaceis composed of a far more liquified and thus a faster, more uniform andmore predictable distribution medium. Delivery of anaesthetics directlyinto the spinal subarachnoid space would therefore be preferable, wereit not for one major side effect. The major problem is the severepost-operative headaches that often result from the puncture of thedural membrane (or dura) upon entrance of spinal catheters and needlesinto the subarachnoid space. Furthermore, the use of catheters andparticularly small-bore catheters has been implicated in suchcomplications as cauda equina syndrome, a neurological syndrome that ischaracterised by loss of sensation or mobility of the lower limbs. InMay 1992, the FDA alerted Anaesthesia Care Providers to the serioushazard associated with continuous spinal anaesthesia by small borecatheters and has taken action to remove all small bore catheters fromthe market. An example of the intrathecal administration procedure isdescribed in U.S. Pat. No. 4,518,383 to Evans.

The current method for intrathecal treatment of chronic pain is by meansof an intrathecal pump, such as the SynchroMed. RTM Infusion System, aprogrammable, implanted pump available from Medtronic Inc., ofMinneapolis, Minn. The system includes a catheter and a pump section.The pump section comprises a collapsible reservoir and a fill port forrefilling the reservoir with fresh drug formulation. The systemautomatically delivers a controlled drug amount through the catheter bymeans of an electric peristaltic pump. The dosage, rate and timing canbe externally programmed using radio waves. The SynchroMed.RTM InfusionSystem thus solves long-term delivery and dosage accuracy problems ofother existing devices. At present the SynchroMed.RTM is used for spinaldelivery of antinociceptive or antispasmodic therapeutics; because ofthe short half-life of these substances they require frequentreadministration, and this is realized by the implanted pump. Although,the system has some major advantages over other existing methods, italso has some disadvantages. One disadvantage is the large, bulky sizeof the SynchroMed.RTM pump. Due to its size, the device must typicallybe implanted in the abdominal cavity of a patient and an extendedcatheter has to be passed through the patient's body to deliver the drugto the desired site of administration. In addition to problems with sizeand placement, the SynchroMed is burdened by complex electronics forboth programming and pumping functionality. Furthermore, complicationsmay arise as a result of the required surgical implantation and thepossibility of leakage of the catheter as well as of the pump.

There is thus a need for an alternative spinal delivery method thatreduces the risks associated with intrathecal drug delivery such aspost-operative headache, meningitis, paralysis and even death byutilising the epidural delivery route. Further there is a need for anovel spinal delivery method that also reduces the surgical risks anddisadvantages seen with implantable pump systems such as theSynchroMed.RTM Infusion System. The present invention discloses a methodand apparatus that relates to controlled and enhanced epidural deliveryof a biologically active agent.

The therapeutic efficacy of numerous highly effective biologicallyactive agents (e.g. large compounds, hydrophilic and charged substancessuch as for example: proteins, (poly) peptides, and nucleotides) islimited, because they cannot or poorly penetrate the epidural space andother biological barriers, resulting in sub-therapeutic drug levelswithin the spinal structures and the brain. Distribution from the matrixof a polymeric implant or catheter of a spinal delivery device is basedon passive diffusion, which is a slow process. During diffusion thecompound (e.g. a peptide) may be subjected to substantial metabolism andclearance. As a result, the volume of tissue exposed to this compound isvery small. Thus, due to the lipophilic nature of the epidural space,transport rate and migration distance of hydrophilic and/or ionisedcompounds within the epidural space is very low. In order to achievetherapeutic adequate levels substantially higher doses will be requiredin comparison to subarachnoid administration. Whereas subarachnoidadministration is a more complicate surgical procedure accompanied withmore risks such as post-operative headache, meningitis, paralysis andeven death.

Therefore, there is also a large interest in development of a spinaldrug delivery method that promotes fast and enhanced transport oftherapeutic agents especially of large, hydrophilic and chargedsubstances to the spinal structures and/or the brain (central nervoussystem, or CNS) for a long term period and that requires a minimum ofsurgical intervention and offers a minimum of side effects.

The present invention overcomes the disadvantages associated withexisting implantable delivery methods such as, bulky reservoirs and/orpumps and the limited drug penetration depth by using phonophoresis oriontophoresis as a drug delivery enhancement technique. Iontophoresishas been defined as the active introduction of ionised molecules intotissues by means of an electric current. Iontophoresis devices requireat least two electrodes, both being in electrical contact with someportion of a biological membrane surface of the body. One electrodecommonly referred to as the “donor” or “active” electrode, is theelectrode from which the biologically active agent, such as a drug orprodrug, is delivered into the body. Another electrode having anopposite polarity functions to complete the electric circuit between thebody and the electrical power source. This electrode is commonlyreferred to as the “receptor” or “passive” electrode. Duringiontophoresis an electrical potential is applied over the electrodes, inorder to create an electrical current to pass through the drug solutionand the adjacent tissue.

Iontophoretic drug administration into body cavities by means of acatheter type of electrode has been first disclosed about 95 years ago.The Russians were in this field very productive and during the 1970'sand 1980's a considerable number of patents were issued (e.g. SU Nos532,890; 843,999; 1,005796). Recently, patents have been issued thatdisclose the treatment of blood-vessel related disorders (e.g.restenosis), bladder, uterus, urethra and prostate disorders.

U.S. Pat. Nos. 6,219,557; 5,588,961; 5,843,016; 5,486,160; 5,222,936;5,232,441; 5,401,239 and 5,728,068 disclose different types ofiontophoresis catheters for insertion into hollow, tubular organs(bladder, urethra and prostate) or into blood vessels.

An implantable system for myocardial iontophoretic delivery of drugs tothe heart is disclosed in U.S. Pat. No. 5,087,243.

Reference may be made to U.S. Pat. No. 5,807,306, which describes aniontophoresis catheter device for delivering a drug contained in apolymer matrix into internal tissue. The disclosed catheter may thus bean ideal tool for selective and controlled delivery to any bodypassageway or hollow organ. Because the drug is contained in a polymericmatrix, the risk of leakage typically associated with catheter devicesis practically negligible. However, the disclosed device is not animplantable device and thus not suitable for long-term treatment.Further, the device requires manual operation.

The method of the present invention allows among other treatments alsofor an improved treatment of chronic pain by means of spinal delivery ofanaesthetics or analgesic agents. At present there are no adequateobjective measures of pain. The drug is being administered largely basedon the sensation of pain expressed by the patient himself. It ishowever, not possible to measure the extent or amount of pain, whereasthis may be of utmost importance for determining the correct drugdosage. It has been suggested that the autonomic nervous system (ANS)may provide information regarding the presence of pain, because the ANSresponds in order to maintain homeostasis within the organism to anyinternal or external stimulus thus also to pain. At present, theassessment of ANS activity is largely focused on the cardiovascularsystem. Unfortunately, cardiovascular measures such as blood pressure,heart rate and heart rate variability are not reliable indicators forthe presence of pain. Skin potentials have been shown to be indicativefor the presence of pain. Skin potentials or the sympathetic skinresponse reflect sweat gland activity and these glands are innervated bysympathetic C-fibers. However, the skin potentials are also largelyinfluenced by the subject's response to emotional stimuli. Thus anyemotional stimuli other than pain will influence the measurement. Otherdisadvantages of skin potentials are the fact that they are unstable andnot reproducible.

I have also discovered the presence of fast oscillating potentialswithin the skin recorded potentials These so-called “fast waves” couldnot be blocked with atropine meaning that they are not transmitted byM-cholinergic sympathetic nerve fibers such as those innervating thesweat glands. The inventor also discovered that the “fast waves” are notsubject to habituation such as “normal” skin potentials do. It has beenhypothesised that these “fast waves” reflect sympathetic activity ofautonomic brain centres that are most likely not located in the limbicsystem and are therefore not influenced by the emotional status of thesubject. The “fast waves” can be recorded from the skin as well as fromany conductive internal body part. It is further suggested that a changein a “fast waves” signal may be used as a tool for pain detection,because they are of autonomic nervous system origin and contain relevantinformation concerning changes in the internal environment. Thedetection of such a change in the “fast waves” could thus provide anexcellent objective measure for the presence of pain and it may even bedetected before the subject has become aware of the pain.

SUMMARY OF THE INVENTION

The present invention relates to a delivery method and device forenhanced and controlled delivery of a biologically active agent into thespinal structures and/or the brain. More particularly, the presentinvention relates to an implantable device comprising an amount of abiologically active agent and transport means for active transport ofthe biologically active agent from the device into the epidural spacefrom where it is actively transported through the dura mater into thesubarachnoid space and into the CNS.

In view of the limitations of existing spinal delivery systems, it is anobject of the present invention to provide a method and device forenhanced and controlled administration of a biologically active agentthat allows for effective concentrations of said agent in the spinalstructures and/or brain following epidural administration.

It is further an object of the present invention to provide a method andan implantable device for administering a biologically active agent intothe spinal structures and/or brain that allows for easy accessibilityand convenient localisation to the site of administration in theepidural space of a mammal and particularly a human being.

It is also an object of the invention to provide an implantable deviceof such design and made of such materials, as well as such a method foradministration of a biologically active agent into the spinal structuresand/or brain through the epidural space that promotes high patientcompliance and acceptance.

It is still another object of the invention to provide a method and animplantable device for administration of a biologically active agentinto the spinal structures and/or brain through the epidural spaceenhanced by iontophoresis and/or phonophoresis that allows for a highlevel of safety with minimal local and systemic side effects.

It is yet another object of the invention to provide a method and devicefor controlled and enhanced delivery of a biologically active agent intothe spinal structures and/or the brain that is regulated by a feedbacksignal.

It is further an object of the present invention to provide an excellentmethod for treatment CNS disorders.

A further object of the present invention is to provide a method anddevice for controlled and enhanced administration of anaesthetics,analgesic or antinociceptive agents in the treatment of chronic painwhereby the delivered dose is regulated by an integrated feedbacksystem.

These and other objects are accomplished by providing an implantabledelivery system based on physical enhancement by means of iontophoresisand/or phonophoresis for delivery of a biologically active agent intothe epidural space and from there into the intrathecal space and intothe CNS thereby essentially avoiding the systemic blood circulation.

For the purpose of this invention, “iontophoresis” is defined as anyform of electrotransport of a substance through mammalian tissue inducedor enhanced by the application of an electrical potential. Thus, theterm “iontophoresis” as used herein includes without limitationpreviously defined terms such as iontophoresis, electrotransport,iontokinesis and electroosmosis, and the combination of thereof, whichcomprises the transport of a substance induced or enhanced by theapplication of an electric potential.

The term “phonophoresis” as used here is defined without limitation asany form of transport of substances that include non-ionized moleculesthrough mammalian tissue induced or enhanced by the application ofultrasound.

As used in conjunction with the disclosed invention, the term“biologically active agent” as defined herein, is an agent, or itspharmaceutically acceptable salt, or mixture of compounds, which hastherapeutic, prophylactic, pharmacological, physiological or diagnosticeffects on a mammal and may also include one compound or mixture ofcompounds that produce more than one of these effects. Suitabletherapeutic, pharmacological, physiological and/or prophylacticbiologically active agents can be selected from the following listed,and are given as examples and without limitation: amino acids,anabolics, analgesics and antagonists, anaesthetics, anti-adrenergicagents, anti-asthmatics, anti-atherosclerotics, antibacterials,anticholesterolics, anti-coagulants, antidepressants, antidotes,anti-emetics, anti-epileptic drugs, anti-fibrinolytics,anti-inflammatory agents, antihypertensives, antimetabolites,antimigraine agents, antimycotics, antinauseants, antineoplastics,anti-obesity agents, anti-Parkinson agents, antiprotozoals,antipsychotics, antirheumatics, antiseptics, antivertigo agents,antivirals, appetite stimulants, bacterial vaccines, bioflavonoids,calcium channel blockers, capillary stabilizing agents, coagulants,corticosteroids, detoxifying agents for cytostatic treatment, diagnosticagents (like contrast media, radiopaque agents and radioisotopes), drugsfor treatment of chronic alcoholism, electrolytes, enzymes, enzymeinhibitors, ferments, ferment inhibitors, gangliosides and gangliosidederivatives, hemostatics, hormones, hormone antagonists, hypnotics,immunomodulators, immunostimulants, immunosuppressants, minerals, musclerelaxants, neuromodulators, neurotransmitters and nootropics, osmoticdiuretics, parasympatholytics, para-sympathomimetics, peptides,proteins, psychostimulants, respiratory stimulants, sedatives, serumlipid reducing agents, smooth muscle relaxants, sympatholytics,sympathomimetics, vasodilators, vasoprotectives, vectors for genetherapy, viral vaccines, viruses, vitamins, oligonucleotides andderivatives, and any therapeutic agent capable of affecting the nervoussystem.

Examples of biologically active agents, which may be preferentiallyadministered using the method disclosed here for enhanced deliverydirectly into the spinal structures and/or brain and thereby essentiallyavoiding the systemic circulation include those biologically activeagents degraded in the gastrointestinal tract, metabolised in aninternal organ or in the blood, rapidly excreted from the bloodstream(e.g. through kidney clearance), and those with limited penetration ofthe blood-brain barrier. Also, those agents with systemic side effectswill benefit from direct administration in the CNS avoiding the bloodstream. Further those biologically active agents that at least partlytarget the CNS although the underlying disease may have systemicclinical manifestations (e.g. alpha-2-agonists and hypertension).

Other objects, features and advantages will be apparent from thefollowing detailed description of preferred embodiments taken inconjunction with the accompanying drawings in which:

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is schematic representation of the drug delivery device of thepresent invention.

FIG. 2A is a schematic side view, partially in section, of a preferredembodiment of the drug delivery system of the present invention in theform of an expandable drug reservoir or drug transfer part and transportmeans (iontophoresis electrode) in its inactivated state, positioned inan elongated tubular body.

FIG. 2B is a schematic side view, partially in section, of a preferredembodiment of the drug delivery system of the present invention in theform of an expandable drug reservoir or drug transfer part and transportmeans (iontophoresis electrode) in its “activated”, expanded state and,the drug reservoir and/or drug transfer part being positioned outsidethe elongated tubular body and in contact with the dura mater.

FIG. 3A is a partial cross-sectional view of another preferredembodiment of the drug delivery device, containing an expandable balloonand electrode that is used to expand the polymer matrix of the drugtransfer part of the drug delivery device. Here the electrode ispositioned in the elongated tubular body, in its non-expanded state whenbeing installed into the epidural space.

FIG. 3B is a partial cross-sectional view of another preferredembodiment of the drug delivery device, containing an expandable balloonand electrode that is used to expand the polymer matrix of the drugtransfer part of the drug delivery device. Shown is its expanded state.

FIG. 4 is a schematic side view of a preferred embodiment of thedisclosed delivery apparatus that has no expandable means.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Practicing the invention involves inserting a donor or active electrodeas by a catheter-based device into the epidural space of a mammal andparticularly a human being. The catheter may be positioned in theepidural space by any one of numerous well-known methods such as forexample the use of a guide wire and fluorescence visualisation. Anotherelectrode being a receptor or passive electrode for iontophoresis may beimplanted in the abdomen or any other internal body location butpreferably in vicinity of the donor electrode. Power to the electrodesis provided to develop an electric field radiating outward from thedonor electrode to the receptor electrode. In order to reduce the riskof cardiac arrhythmia when the electrodes are in the region of theheart, the current to the electrodes may be pulsed on during systolephase of cardiac pumping and off during diastolic phase. The electricfield will cause the biologically active agent to permeate outwardlyfrom the donor electrode toward the receptor electrode thus causingtransport of the biologically active agent through the epidural space,dura mater, subdural space and eventually through the arachnoid membraneinto the intrathecal space from where it may travel to other spinalstructures and into the CNS.

The term “catheter” as used in the present invention is intended tobroadly include any medical device designed for percutaneousintroduction and insertion into a body passageway or a localised area ofinternal tissue to permit injection or withdrawal of fluids, to keeppassage open, to deliver drugs or other therapeutics, or for any otherpurpose. For purposes of this invention, a catheter is not necessarilytubular. It is contemplated that the drug delivery apparatus of thepresent invention has applicability for use in the epidural space of amammal and particularly a human being.

The preferred drug transport means is iontophoresis which facilitatesboth transport of the drug out of the device and/or tissue penetration,including the epidural space, dura mater, subdural space, arachnoidmembrane, subarachnoid space, pia mater and other nervous tissue in thespinal region and further the CNS. Another preferred drug transportmeans is phonophoresis. In a yet other preferred embodiment the drugtransport means is iontophoresis in combination with phonophoresis.

In accordance with the method of the present invention there is providedan implantable catheter-based device for enhanced and controlleddelivery of a biologically active agent comprising a donor electrodehaving an electroconductive member and a drug reservoir or drug transferpart that is in electric contact with the electroconductive member. Thedrug reservoir or drug transfer part may be expandable or may be part ofan expandable member in order to make an intimate contact with the duramater. This is relevant for those embodiments that are based oniontophoretic delivery of a biologically active agent directly throughthe dura mater. The device further comprises a receptor electrode havingan electroconductive member and an electrolyte-containing compartment.The device according to the present invention further comprises a powercontrol unit (PCU) having integrated a (pre)-programmable power source,which is operated by a microprocessor or microchip and that furtherincludes means for storing and/or transmitting data for example bytelemetry. The power control unit is electrically connected to the donorand receptor electrodes.

The PCU can be programmed to deliver any type of current waveform as forexample, direct current or alternating current and the current may haveany frequency depending on the compound to be delivered and thetreatment that requires delivery of said compound. The current strength,duration of current application and location of the receptor electrodemay be varied to further focus the flow of the biologically activeagent. Thus the direction and uniformity of dispersion and permeation ofthe biologically active agent may be controlled. The polarity of thedonor and receptor electrode is selected with reference to the sense ofthe ionic compound. The current strength delivered to the donor andreceptor electrodes ranges between 0.001 to 10 mA/cm², and is preferablyselected from the following range of 0.01 to 1.0 mA/cm².

In a preferred embodiment of the present invention the PCU can beexternally programmed in order to adjust the delivery dose of thebiologically active agent by a physician. Optionally, the deliverydevice may comprise means for telemetry that allows the physician toreceive operational information of the device from a remote site.

In another embodiment the delivery device may comprise a source ofthermal energy. Such a source can, of course also be combined with theelectric current or ultrasound source. For example, a combination of asource of electric energy and a source of thermal energy has theadvantage that a compound with a relatively high molecular weight can bedelivered in a mammal, because the supply of thermal energy will allow abetter penetration into tissues due to dilatation effects.

The donor electrode of the implantable device as disclosed in thepresent invention consist of a drug reservoir or drug transfer part,which can release the biologically active agent over an extended periodof time while at the same time preserving the bioactivity andbioavailability of the biologically active agent.

After positioning of the catheter-based device in the epidural space,the donor electrode is advanced outward of the device thereby exposingat least partly the drug delivery part of the device into the epiduralspace. Upon application of an electric field or ultrasound thebiologically active agent is actively transported out of the device andtravels under influence of the electric field or the applied ultrasoundvia the epidural space in a direction of the spinal cord to the adjacentspinal tissues and into the brain.

In an expedient embodiment of the disclosed method, the delivery part ofthe catheter-based device is arranged and constructed in such a way andhaving such a shape that it is adapted to make an intimate contact withthe dura mater. Upon application of an electric field or ultrasound thebiologically active agent is then actively transported out of the deviceand will travel under influence of the electric field or the appliedultrasound through the dura mater into the adjacent spinal tissues.

According to an alternate embodiment of the disclosed method, thedelivery device comprises a biosensor that is connected to the PCU. Thebiosensor may detect any physical or chemical signal upon which the PCUstarts, continues and/or modifies or interrupts a delivery program. Inthis way a feedback mechanism is provided that automatically controlsthe output current while for example monitoring the physiologicalcondition of the treated subject. An example of the use of such afeedback mechanism is the detection of pain by using signal analysis ofthe sympathetic “fast waves” during delivery of analgesics in thetreatment of chronic pain. The sensor detects these potentials and theyare processed and integrated within the PCU by a microprocessor that onits turn uses the processed information as a signal to start, modify orinterrupt a particular current delivery program. Normalisation of thesignal can be used as indicator for the PCU to stop a particulardelivery program.

The biosensor as used in the present invention may be selected from thetype of sensors that are sensitive for the following non limitingsignals known to those skilled in the art: physical (e.g. temperature,pressure, current strength, potentials as fast waves, skin potentials,EEG, ECG etc.) or chemical (e.g. pH, electrochemical potential,concentration, etc.). Any appropriate sensor may be integrated in orconnected to the delivery device according to the present invention andthe type of sensor being dependent on the purpose of the deliveryapplication.

In an alternative embodiment, the receptor or passive electrode maycomprise a plurality of implanted electrodes (more than one) withpreferred site of positioning on the ventral site of the vertebralcolumn as for example the abdomen. The positioning of the receptorelectrode is crucial, because it has to create a vector of electricalfield in such direction that it facilitates transport of thebiologically active agent from the administration site into the spinalstructures and/or the brain.

According to yet another embodiment the receptor electrode (s) may bepositioned external (e.g. on the skin) of a mammal's body.

The biologically active agent may be delivered by means of acatheter-based device using several different embodiments. In oneembodiment, which may be used with any of the catheter embodiments setforth, the biologically active agent is incorporated within a polymermatrix, and this matrix may optionally be applied as a coating on anexpandable member of the delivery device. The polymer matrix preferablyhas good drug holding capacity.

In another embodiment, microspheres incorporating the biologicallyactive agent may be used for delivery of said agent. The drug-ladenmicrospheres may then be injected in the epidural space, near the duramater and activated by the catheter thereby driving the biologicallyactive agent from the microspheres into the dura mater and the adjacentspinal tissues. Microspheres useful in the present invention includethose sold under the name biSphere. TM. available from POINT Biomedical(San Carlos, Calif.).

Additionally, normal drug delivery means may be used as well, such asfree liquid form. However, use of polymer matrices has certainadvantages over free fluid delivery. Delivery of a biologically activeagent, which is contained in a polymer matrix, does not requireadditional lumens in the catheter to transport the liquid drug solutioninto and out of the delivery site. Additionally the polymer matriceseliminate the risk of downstream leakage of drug solution, therebyavoiding the risk of exposure of non-target tissue to highconcentrations of the biologically active agent. Importantly there willalso be no need for implanted pumps that re-administer the drug solutionto the implanted catheter and its reservoir Also, since no extra lumensin the catheter are required, the device is narrower and this improvesits maneuverability in the body and reduces its production costs.

In an alternate preferred embodiment the device according to the presentinvention has a mean that allows for in situ refilling of the drugreservoir or drug transfer part. Re-filling methods and devices are wellknown to those skilled in the art and mechanisms that prevent leakage,back flow of liquid into the filling tube and other problems associatedwith refillable implants may be used and are well known to those skilledin the art and are enclosed herein their entirety. However, it isexpected that the drug reservoir or drug transfer part of the implanteddelivery device having an appropriate size could release sufficientquantities of the biologically active agent for at least one year,because the absolute amounts of most biologically active agents requiredfor spinal delivery are very small.

Preferred embodiments of the invention as well as alternativeembodiments will be described in detail with reference to the drawings.

In FIG. 1 there is shown a schematic representation of the deliverydevice. In this FIG. a device is shown that is especially suitable forlong-term epidural placement. The three basic components of the deliverydevice i.e. donor 1 and receptor 3 electrodes and the PCU 2 arecontained in insulating and non-degradable, biocompatible housings. ThePCU is electrically connected with the two electrodes by insulatedelectric wires 14.

In order to provide an intimate contact with the dura mater the drugdelivery part or drug transfer part may be expanded. The means ofexpansion of the drug delivery part of the device according to thepresent invention include without limitation the following:

1. The drug transfer part becomes expanded due to pushing into itscentral space or potential space the central piece 8, which could alsoserve as an electrode that could be shaped as a rod or have anothershape or design such as a spring loaded or manually loaded wire basketof various shapes obvious to those skilled in the art, into the interiorchamber 11 of the drug transfer part 13 (FIG. 2A; non-expanded, and FIG.2B; expanded). The drug reservoir or drug transfer part of the drugdelivery device is advanced out of the catheter shaft 5, whereafter themiddle piece 8 is pushed into the drug transfer part by a wire or rod 6,that may be attached to a handle of the device outside the epiduralspace. The part of the expandable device not involved in drug transferis composed of an insulating, impermeable and biocompatible material(e.g. polymer) 12. The means of expansion is preferable supplied withappropriate markings to indicate the amount of expansion of theexpandable part of the device. The middle piece 8 comprises a part thatis not electroconductive 10 and an electroconductive part 9 that servesas an electrode for iontophoresis and is via 6 and 14 connected to thePCU 2. The PCU may be placed at any convenient internal position; theelectric circuit is completed by connection of the receptor electrode(s)3 on a pre-determined location internal to the body (e.g. within theabdominal region just under the skin but outside the peritonealmembrane) or optionally on a determined external location of a human orother mammal's body, e.g., just outside the skin over the abdominalregion.

The wire or rod 6 may be used to conduct current to the electrode 9after the electrode is in place. When the device has to be removed, themiddle piece 8 is removed from the expandable member of the deliverydevice and is preferably pulled into holding chamber 4 using wire 6.This allows the delivery device to assume its narrower profile, whichaids in the removal of the device from the epidural space. Optionalimpermeable end caps 7 are provided at both anterior and posterior endsof the drug transfer part to prevent inadvertent drug leakage as well asto prevent delivery of the biologically active agent into non-targettissue. The posterior end caps are constructed in such a way to preventthe central piece to be pushed too far through the electrode space 11,outside markers indicate the position of the middle piece 8.

2. Alternatively to mechanical induced expansion, the polymeric matrixof the drug reservoir has reversible swelling properties induced byelectric current, pH, temperature or any combinations thereof or by anyother possible chemical or physical parameter, which may inducereversible swelling of the polymeric drug reservoir, known to thoseskilled in the art.

3. The drug reservoir or drug transfer part becomes expanded due toinflation of a preferably cylindrical shaped balloon on which the drugcontainer (e.g. a polymer matrix) is located. An electrode covers theballoon for example in its medial aspects, thereby allowing for enhancedtransport out of the drug transfer part and directly into the epiduralspace. The electrode may be expandable (e.g. a wire mesh), and may takeany form obvious to those skilled in the art. In one example, theballoon 22 is inflated by fluid or gas through lumen 20 (FIG. 3A). Inits expanded state (FIG. 3B) electrode 23 expands with balloon 22. Thepart of the electrode that is in touch with the balloon or any otherexpandable mean is composed of a layer of insulating material. Thepolymer matrix 13 serves as a drug reservoir or drug transfer part inthis example. Electric current is provided to the electrode 23 usingwire 24, which runs alongside lumen 20.

The membrane that comprises the wall of the balloon is preferably madeof an impermeable material (prevents the flow of water or electrolyteand any component of the drug transfer part or reservoir in anydirection).

The drug delivery part of the device is shaped following expansionaccording to the human epidural space in order to provide the best fitin the epidural space, which is necessary for an intimate contactbetween the device and the dura mater.

The balloon is attached along either anterior or posterior end to thebody of the device using an adhesive or heat weld or other means knownto those skilled in the art. The drug reservoir or the drug transferpart is disposed on the outer surface of the balloon that is positionedtowards the spinal cord for intimate contact with the dura mater afterexpansion. In use, the balloon 22 is expanded with a fluid suppliedthrough fluid-supply lumen 20. The fluid used to expand the balloon 22is water, or a solution, preferably an aqueous-based solution, morepreferred an electrolyte solution such as sodium chloride (saline), mostpreferably a weak electrolyte solution. However, the balloon 22 may beexpanded with any possible fluid or gas for use in catheters withexpandable means known to those skilled in the art, but preferablysuitable to provide for long-term inflation such as required for useaccording to the present invention.

In an alternative embodiment the device is substantially similar to thedevice shown in FIG. 2 but with the substitution of an ultrasoundtransducer for the electrode 9. The iontophoresis electrode is replacedby an ultrasonic piezoelectric transducer (barium titanate, leadzirconate titanate, or the like), which is connected to the PCU. Afterthe drug delivery device is in place, the ultrasonic transducer isactivated to transport the biologically active agent into thesurrounding spinal structures and the brain. The transducer is used toproduce sonic energy, which moves the biologically active agent directlyfrom the drug transfer part 13 to the dura mater, and/or enhancepenetration of the biologically active agent through the dura mater andinto the adjacent spinal tissues as well as into the CNS. Any type ofdrug reservoir or drug transfer part containing the drug transfersurface disclosed above can be used instead of the polymer matrix. Here,phonophoresis is used instead of iontophoresis.

In another preferred embodiment, the drug delivery device includes aflexible body and a drug reservoir or a drug-containing transfermaterial comprising a drug transfer surface (e.g. composed of a polymermatrix). Positioned in the polymer matrix is an electrode, which isconnected to a wire, which extends to the proximal end of the tubularmember. Instead of the polymer matrix, any material can be used butpreferably that with good elastic properties so that it can assume theshape of the epidural space in order to provide an intimate contactbetween the drug transfer surface and the dura mater. Any design, sizeor material of the electrode known to those skilled in the art can beused in this embodiment but the important feature is that the devicefits comfortably and for a long time period into the epidural space ofthe subject and provides an intimate contact with the dura mater.

FIG. 4 shows an example of a device that could implement the disclosedmethod without expandable means. There is shown a proposedcatheter-based drug delivery device that is arranged and constructed insuch a way that it can be optimally positioned into the human epiduralspace for iontophoretic and/or phonophoretic transport of a biologicallyactive agent through the dura mater into the adjacent spinal structuresand brain. The donor electrode of the drug delivery device is advancedout of the catheter when it has reached the epidural space and when ithas assumed the correct orientation. Alternatively, the catheter itselfmay be removed and leaving the donor electrode implanted. The donorelectrode comprises an electrode 30 having an electroconductive part 31and an electric insulating backing layer 32 that is impermeable andbiocompatible. The drug reservoir or transfer part 33 being preferably apolymer matrix that is capable to release the biologically active agentupon application of an electric field. Most preferably, the drugreservoir has such properties that it is only permeable for drug andelectrolyte transport during current application and is impermeable forboth electrolytes and the biologically active agent when there is nocurrent transport.

In addition, drug reservoirs and/or drug transfer parts, which can befilled with a liquid composition containing the biologically activeagent through additional lumens (extending from the proximal end towardsthe drug reservoir and/or drug transfer part at the distal end of thedevice) may be used. Thereby allowing the liquid composition in the drugreservoir or drug transfer part of the device to be replacedcontinuously or at appropriate times. Thus providing an alternative drugdelivery system, which can be used for long-term, enhanced drugdelivery.

With respect to the polymer composition, the term “polymer matrix” asused herein includes synthetic hydrogel polymers with pores orinterstices of different sizes and capacities introduced duringmanufacture, and a variety of synthetic elastomers and naturallyoccurring polymeric materials known to those skilled in the art. Thebiologically active agent can be incorporated in the matrix eitherduring polymer production or added after coating or molding of thepolymer into the desired shape. Additionally, many of a number ofdifferent polymeric materials and methods of fabrication may be used toform the polymeric matrices used in the present invention. Examples ofsuitable polymer materials or combinations include, but are not limitedto, biocompatible and/or biodegradable polymers such as poly (lactides),polyglycolides, polyanhydrides, polyorthoesters, polyactals,polydihydropyrans, polycyanoacrylates and copolymers of these andpolyethylene glycol. These can take the form of copolymer hydrogels orcross-linked polymer networks into which drugs for electrically enhancedlocal delivery can be incorporated either during polymerisation or, inthe case of certain hydrogels, loaded subsequently. Preferable matriceswould be tailored according to the molecular characteristics of theagent to restrict its loss by free diffusion outwards, but allow fulliontophoretic migration outwards when a potential is applied across thepolymer and adjacent tissue.

With respect to the electroconductive members or electrodes, which canbe used in the present invention, they are comprised of electricallyconductive material such as a metal like aluminium, stainless steel,gold, silver, titanium, and zinc. Examples of other suitableelectrically conductive materials include but are not limited to:carbon, graphite, and metal salts like silver chloride. Electrodes maybe formed of metal foil, metal screen, metal deposited or painted on asuitable carrier backing by means of calendaring, film evaporation, orby mixing the electrically conductive material in a polymer bindermatrix. Alternatively, electrodes may be formed of a polymer matrixcontaining conductive filler such as a metal powder, powdered graphite,carbon fibers, or other known electrically conductive filler material.Polymer based electrodes may be manufactured by mixing the conductivefiller in a polymer matrix, preferably a mixture of hydrophilic andhydrophobic polymers. The hydrophobic polymers provide structuralintegrity, while the hydrophilic polymers may enhance ion transport. Forexample, metal powder, carbon powdered, carbon fibers and mixturesthereof can be mixed in a hydrophobic polymer matrix.

The donor and receptor electrode can be made of any suitable material orcombination of materials, that fulfils relevant criteria with respect tocompatibility with the biologically active agent in case of a donorelectrode and with the biological environment, but also with respect toease of manufacturing, sterilizability, re-usability, low environmentalimpact, flexibility, connectibility, disposability and durability.Furthermore, in case of a reservoir-type electrode, the reservoircontaining the biologically active agent should be constructed of anymaterial in such way that it is adapted to absorb and hold a sufficientquantity of liquid in order to permit transport of the active agentthrough its wall by means of iontophoresis. For example sponges, gauzesor pads consisting of cotton or other absorbent fabric, either ornatural or synthetic origin, may be used.

More preferably, reservoirs are composed, at least in part, of one ormore hydrophilic polymers. Typical preference is for hydrophilicpolymers because water is the preferred ion transport medium andhydrophilic polymers have relatively high equilibrium water content.Multilayered solid polymer reservoir matrices are composed, at least inpart of hydrophilic polymer. The form, size and shape of the donorelectrode and its drug reservoir are determined by the physiological,anatomical environment related to the application site.

In one embodiment of the device, solid or semisolid material(s) is usedas the drug reservoir and/or drug transfer part (e.g. gel, polymermatrix or membrane) when located in the expandable part of the device itshould be made of a compliant and expandable material (regardless of themechanism of expansion), ideally minimally compressible. Thecompressibility of the material is preferably limited to ensure intimatecontact between the drug transfer surface and the dura mater to enhancedrug transfer and decrease side effects. In an alternative embodiment,the material could be compressible, provided the expandable part isdesigned in such a way that there is intimate contact after expansiondespite of the compressibility of the material.

In the embodiments, which do not expand, radial, the material does notneed to be expandable. However, in such embodiments the plasticityproperties of the material are important and the material may becompressible in order to better mold to the anatomy of the epiduralspace and preferably to provide a better contact interface with the duramater.

In a preferred embodiment, the drug transfer surface is located in theexpandable part, which allows radial or unidirectional (ventral i.e.towards the dura mater) expansion of the device or part of the devicecontaining the drug transfer surface after the device has been advancedto an appropriate depth so that following expansion the drug transfersurface forms an intimate contact interface with the dura mater.

The power supply used in conjunction with the present invention can beany small-size and lightweight cell. For example, the cells includemanganese cells, alkali cells, lithium cells, unicad cells, silver oxidecells, mercury cells, air cells, alkali-manganese cells and plasticcells. Plastic cells are formed into button shape or sheet.

The drug reservoir or drug transfer part or other contact surface thatis directly involved in the drug transfer of each of the describedpossible embodiments may optionally contain penetration enhancingsubstance(s) and/or enzyme inhibitors, either as part of thepharmaceutical composition or as part of the polymer matrix or drugreservoir membrane or drug transfer part of the device, to furtherenhance the drug transport through the epidural space or dura mater intothe adjacent spinal tissue and into the CNS.

The drug delivery device is positioned within the tubular member duringits installation to the target area in the epidural space. The drugreservoir or drug transfer part of the disclosed drug delivery devicecan be placed by pushing the drug delivery device out of the tubularbody until it reaches a predetermined point beyond the drug deliverydevice may not be further advanced outwards. The elongated tubular bodythus provides a means of protection to the drug delivery device andespecially to the drug reservoir or drug transfer part, duringinstallation and removal of the device. It will be understood, thatinstead of pushing the drug delivery device out of the tubular member,the latter can also be pulled back to expose the drug reservoir or drugtransfer part in the epidural space, which will in possible alternativeembodiments of the present invention lead to a comparable result.

The tubular body being constructed from electrically insulating,biocompatible material and further being flexible to facilitate theinsertion through the narrow epidural space.

Alternative to the described tubular body, it may be equipped with meansto allow for endoscopic controlled installation of the drug deliverydevice. For example, it may contain besides the drug delivery device anoptic fiber or any other possible imaging means known by those skilledin the art.

In another preferred embodiment of the present invention, the drugdelivery device or a part of it i.e. the drug reservoir or drug transferpart is placed at its target site in the epidural space, whereas thetubular body is removed. The drug delivery device or a part of it maythus be implanted in the epidural space but be connected to the PCU. Atappropriate times, depending on the treatment the device or part of itis replaced. The device or part of it may be placed at its target sitepossibly under endoscopic control by means of sutures, adhesives orother semi-permanent or permanent connections.

It will now be apparent to those skilled in the art that otherembodiments, improvements, details, and uses can be made consistent withthe letter and spirit of the foregoing disclosure and within the scopeof this patent, which is limited only by the following claims, construedin accordance with the patent law, including the doctrine ofequivalents.

1. A method for enhanced and controlled delivery of a biologicallyactive agent into the spinal structures and/or the brain of a mammal,particularly a human being that circumvents the blood brain barrier,which includes the steps of: providing an agent drug delivery device viacatheter to the epidural space of the mammal and positioning said devicewithin the epidural space, advancing a donor iontophoresis electrodeinto the epidural space of the mammal, applying a second electrode orreceptor iontophoresis electrode that is constructed and arranged to bepositioned at a determined internal or external position of the mammal'sbody but in complementary energy gradient positioning to the firstelectrode, providing a potential gradient so that delivery of thebiologically active agent is accomplished in a direction from said firstelectrode means directly into the spinal structures and/or the brainthereby essentially bypassing the blood brain barrier of the mammal; andthereby, delivering said biologically active agent directly to thespinal structures and/or to the brain of said mammal.
 2. A method forenhanced and controlled delivery of a biologically active agent into thespinal structures and/or the brain of a mammal, particularly a humanbeing that circumvents the blood brain barrier, which includes the stepsof: providing an agent drug delivery device via catheter to the epiduralspace of the mammal and positioning said device within the epiduralspace, advancing a phonophoresis device in the epidural space of themammal, providing an energy gradient so that delivery of thebiologically active agent is accomplished in a direction from saidphonophoresis device directly into the spinal structures and/or thebrain thereby essentially bypassing the blood brain barrier of themammal, and thereby, delivering said biologically active agent to thespinal structures and/or to the brain of said mammal.
 3. A method asclaimed in claim 1 wherein a biosensor is used for feedback regulateddelivery of the biologically active agent to the spinal structuresand/or brain of the mammal.
 4. A method as claimed in claim 3 whereinthe biosensor is used for feedback regulated delivery of thebiologically active agent in the treatment of chronic pain.
 5. A method,using an implantable device, for enhanced and controlled delivery of abiologically active agent into the spinal structures and/or the brain ofa mammal, particularly a human being, and that circumvents the systemiccirculation, which comprises the steps of: (i) directing at least oneend of a catheter containing a delivery device to the epidural space ofa mammal and positioning said catheter and delivery device within theepidural space to provide an effective arrangement for delivering abiologically active agent which is contained in said device into themammal; (ii) advancing a first electrode from said delivery device thatis constructed and arranged to be positioned in the epidural space of amammal into the epidural space of a mammal and act as a donor electrode;(iii) applying a second electrode that is constructed and arranged to bepositioned at a determined internal or external position of the mammal'sbody and act as a receptor electrode; (iv) electrically connecting saidfirst and second electrodes to a power control unit that includes anintegrated (pre)-programmable power source, the power source beingoperated by a microprocessor, said power source providing a potentialgradient so that delivery of a biologically active agent is accomplishedin a direction from said first electrode directly into the spinalstructures and/or the brain thereby essentially bypassing the systemiccirculation of a mammal; and (v) delivering said biologically activeagent to the spinal structures and/or to the brain of said mammal usingan active transport means.
 6. A method according to claim 5 wherein theactive transport means is iontophoresis and/or phonophoresis.
 7. Amethod according to claim 5 wherein said power source provides anelectro-potential gradient or ultrasound.
 8. A method as claimed inclaim 5 wherein a biosensor is connected to the power control unit forfeedback regulated delivery of a biologically active agent to the spinalstructures and/or the brain of a mammal.
 9. A method as claimed in claim8 wherein the biosensor is adapted to register biopotentials forfeedback regulated delivery of a biologically active agent in thetreatment of chronic pain, hyperkinesis or any other pathologicalsymptoms or diseases.
 10. A method as claimed in claim 5 wherein thedonor electrode includes a drug reservoir or drug transfer part forstorage of the biologically active agent, an impermeable part that isnot involved in drug transfer, and an electroconductive member.
 11. Amethod as claimed in claim 5 wherein the receptor electrode is aniontophoresis electrode which includes an electrolyte-containingcompartment for storage of electrolyte, an electroconductive member anda membrane through which electrolyte transport occurs.
 12. A methodaccording to claim 5 that includes a means for in situ refilling of saiddevice.
 13. A method as claimed in claim 5 wherein the donor electrodeincludes a means for expansion thereby allowing the drug reservoir ortransfer part to make an intimate contact with the dura mater.
 14. Amethod as claimed in claim 5 wherein an expansion means is operablyconnected to the drug delivery device, the expansion means beingconfigured to expand the donor electrode in a direction substantiallyradial thereby promoting an improved contact interface between the drugreservoir or transfer part and the dura mater.
 15. A method as claimedin claim 12 wherein an expansion means is provided by reversibleswelling properties of the drug reservoir or transfer part that isinduced by chemical or physical changes such as for example, electriccurrent, pH, temperature or any combinations thereof.
 16. A method asclaimed in claim 5 wherein the drug delivery part of the device isshaped following expansion according to the human epidural space.
 17. Amethod according to claim 5 wherein said first electrode is areservoir-type iontophoresis electrode holding a supply of the selectedbiologically active agent in a formulation suitable for iontophoretic orphonophoretic delivery and/or wherein said second electrode is areservoir-type iontophoresis electrode holding a supply of electrolyte.18. A method according to claim 5, wherein said first and secondelectrodes comprise an electroconductive part having electroconductivematerial selected from the following group: stainless steel, gold,silver, titanium, copper, zinc, graphite and metal salts (e.g. silverchloride).
 19. A method according to claim 5 wherein said reservoir ofsaid first and/or second electrode means is formed of a polymer matrixcontaining an electroconductive filler material selected from the groupconsisting of a metal powder, powdered graphite and carbon fibers.
 20. Amethod according to claim 17 wherein said reservoir is constructed ofmaterial that is adapted to absorb, hold and release the biologicallyactive agent and/or electrolyte.
 21. A method according to claim 17wherein said reservoir is made of a hydrogel that holds the biologicallyactive agent and/or electrolyte.
 22. A method according to claim 5wherein the catheter-based device includes a mean for endoscopiccontrolled installation such as an optic fiber.
 23. A method accordingto claim 5 wherein the catheter-based device can be removed entirelyfrom the epidural space following positioning of the donor electrode.